Traumatic brain injury (TBI) is the primary cause of death and disability in young adults and children. It occurs every 21 seconds and afflicts up to two million people annually in the United States. TBI is a heterogeneous insult that precipitates a cascade of ripples that propagate severe long-lasting pathologies. The limbic hippocampus, a brain structure crucial for learning and memory is often damaged in TBI. It is still unknown how regional changes in cellular metabolism and neurotransmitter function contribute to cognitive impairment associated with TBI. However, our preliminary data suggest that post-traumatic regional shifts in hippocampal excitability are due in part to a change in metabolic priorities. Our key observation is that specific amino acids normally employed for neurotransmitter synthesis are potentially diverted to protein synthesis and catabolism for energy thus disturbing the necessary balance between excitation and inhibition. Significantly, dietary administration of branched chain amino acids (BCAAs) after injury results in comprehensive cognitive restoration. We have thus formulated the following CENTRAL HYPOTHESIS: Dietary intervention with branched chain amino acids restores posttraumatic cognitive deficit by ameliorating regional shifts in hippocampal excitability. To test this hypothesis, cellular metabolism, as well as excitatory and inhibitory function in hippocampal subregions will be studied from the molecular to the systemic level in a mouse model of TBI. Better understanding the temporal window and mechanism(s) contributing to our successful dietary intervention will enable the specific formulation of the most efficacious future intervention to alleviate this devastating (i.e. cognitive impairment) pathology. PUBLIC HEALTH RELEVANCE: Traumatic brain injury (TBI) is a major public health issue, which has a significant impact upon our healthcare system. Economic analyses of the annual cost of TBI-related disabilities range from $4.5 billion in direct expenditure (medical care and services) to $20.6 billion in injury-related work loss and disability. Our long-range goal is to continue to formulate an efficacious, safe and well- tolerated dietary intervention that can be rapidly translated from the bench to the clinic to ameliorate cognitive dysfunction in TBI patients.